Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression.
Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression.
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发表时间：
1996-09
期刊：
影响因子：
4.6
通讯作者：
G. Benson;H. Lim;B. Paria;I. Satokata;S. Dey;R. Maas
中科院分区：
文献类型：
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作者：
G. Benson;H. Lim;B. Paria;I. Satokata;S. Dey;R. Maas
建立一个可接受的子宫环境是胚胎存活和着床的关键。在小鼠的植入期子宫中表达的一个基因是雌性生育所必需的同源盒基因Hoxa-10。在这里，我们描述了Hoxa-10突变女性的着床周围缺陷，并研究了Hoxa-10在形态发生期间和怀孕期间在子宫基质和成年子宫中的功能。对Hoxa-10突变女性的妊娠检查显示，植入失败以及胚胎在植入后早期的吸收。变异子宫的形态学分析显示近端25%的子宫同型转化为输卵管。组织学和分子标记证实了这种前向转变。此外，原位杂交表明，该区域与胚胎Hoxa-10在泌尿生殖道表达的前边界一致，并且在Hoxa-10突变雄性的附睾和输精管交界处观察到平行转化。女性的生育能力可能受到同型变异或Hoxa-10功能缺失的影响。为了区分这两种潜在的不孕机制，在假妊娠第2.5天将野生型囊胚转移到突变的子宫远端。这一过程并没有挽救表型，表明成年子宫表达Hoxa-10在怀孕期间是必需的。此外，当着床被实验延迟时，纯合子子宫能够支持囊胚的存活，与野生型对照相当，这表明对Hoxa-10的需求是着床所固有的。虽然在突变的子宫中，LIF和HB-EGF的表达没有受到影响，但蓝色染料反应的强度和数量有所下降，这是对植入反应的血管通透性增加的一个指标。此外，突变的子宫在人工刺激下表现出减少的去个体化。这些结果表明，Hoxa-10在生殖系统的形态形成和成人子宫的植入期事件中是必需的。
The establishment of a receptive uterine environment is critical for embryonic survival and implantation. One gene that is expressed in the uterus during the peri-implantation period in mice and is required for female fertility is the homeobox gene Hoxa-10. Here we characterize the peri-implantation defects in Hoxa-10 mutant females and investigate functions of Hoxa-10 in the uterine anlage during morphogenesis and in the adult uterus during pregnancy. Examination of pregnancy in Hoxa-10 mutant females has revealed failure of implantation as well as resorption of embryos in the early postimplantation period. Morphologic analysis of the mutant uterus has demonstrated homeotic transformation of the proximal 25% into oviduct. Histology and molecular markers confirm this anterior transformation. Furthermore, in situ hybridization shows that this region coincides with the anterior limit of embryonic Hoxa-10 expression in the urogenital ducts and a parallel transformation is observed in Hoxa-10 mutant males at the junction of the epididymis and ductus deferens. Female fertility could be compromised by either the homeotic transformation or the absence of Hoxa-10 function in the adult during pregnancy. To distinguish between these two potential mechanisms of infertility, wildtype blastocysts were transferred into mutant uteri distal to the transformed region on day 2.5 of pseudopregnancy. This procedure did not rescue the phenotype, suggesting that adult uterine expression of Hoxa-10 is required during pregnancy. Moreover, when implantation was experimentally delayed, homozygous uteri were able to support survival of blastocysts comparable to wild-type controls, indicating that the requirement for Hoxa-10 is intrinsic to implantation. While expression of LIF and HB-EGF appears unaffected in the mutant uteri, a decrease is observed in the intensity and number of blue dye reactions, an indicator of increased vascular permeability in response to implantation. In addition, mutant uteri exhibited decreased decidualization in response to artificial stimuli. These results show that Hoxa-10 is required during morphogenesis for proper patterning of the reproductive tract and in the adult uterus for peri-implantation events.